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RED - Chemistry > Peptides and Protein Chemistry 2; Protein Structure, Folding, Insulin. > Flashcards

Peptides and Protein Chemistry 2; Protein Structure, Folding, Insulin. Flashcards

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1
Q

What different functional ways can proteins be described by?

A
  • Enzymes; accelerate biochemical reactions
  • Structural; form biological structures
  • Storage; of AAs
  • Transport; carry important substances
  • Hormonal; coordination of organism’s activity
  • Receptors; signal transduction
  • Motor proteins; movement
  • Defense; immune system
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2
Q

What are the different ways you can classify a protein by its structure/shape?

A
  • Globular ‘spherical’; many different folds (tertiary structuers)
  • Fibrous; extended shape, generally structural proteins
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3
Q

How can proteins be classified in terms of cell localisation?

A
  • Membrane; in direct physical contact with a membrane, generally water insoluble
  • Soluble; water soluble, can be anywhere in the cell e.g. nucleus, cytosol.
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4
Q

What is the structure of a protein determined by?

A

Its amino acid sequence; primary structure

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5
Q

What is the function of a protein determined by?

A

Its shape; tertiary and sometimes quaternary structure

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6
Q

What is meant by a ‘sequence motif’?

A

Clusters of conserved residues within the sequence; carrying out a particular function/form a particular structure that is important for the protein, conserved between different species.

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7
Q

What is meant by absolute/similar/non-conservation of a protein’s surface? Where does insulin fit-in?

A
  • Absolute; residue is always the same e.g. Asp
  • Similar; residue is generally similar e.g. negatively charged
  • Non-conservation; different residue in different species

Insulin is highly conserved; porcine and human insulin only differ in a single AA and bovine by 3 AAs.

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8
Q

What techniques can be used to determine protein structure?

A
  • X-ray crystallography

- NMR spectroscopy

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9
Q

What covalent protein structure stabilising forces exist?

A
  • Peptide bonds

- Disulfide bridges

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10
Q

What noncovalent protein structure stabilising forces exist?

A
  • Hydrogen bonds
  • Van der Waals
  • Hydrophobic interactions
  • π-π overlap (e- delocalisation)
  • Electrostatic interactions (ionic and salt bridges)
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11
Q

Where are peptide bonds present and how can they be broken?

A
  • Between AAs
  • Broken down to individual AAs by:
    > hydrolysis in harsh chemical conditions with 6M acid/alkali,
    > proteases/proteolytic enzymes under physiological conditions
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12
Q

Where are disulfide bonds present and how can they be broken?

A
  • Between two Cys residues via thiol (R-SH) groups

- Broken down by reduction with β-mercaptoethanol reforming cysteines

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13
Q

How strong is a H-bond/what influences the strength, and how are they disrupted?

A
  • Depend on angle; optimum orientation requires X-H to point directly to lone pair (2 - 25 kJ mol-1)
  • Disrupted by heat
  • N, O, F = H-bond acceptors (lone pairs) and donors if H attached
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14
Q

How strong are van der Waals interactions, where do they occur and how can they be disrupted?

A
  • 0.5 - 4 kJ mol-1
  • Interactions between close atoms (short range dipole-dipole)
  • Easily disrupted by heat or denaturing agents
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15
Q

Where does π-π overlap occur and how is it disrupted?

A
  • Between π electron clouds delocalised over rings + bonds

- Disrupted by heat

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16
Q

How strong are electrostatic bonds/ionic interactions/salt bridges and how are they broken?

A
  • 25 - 50 kJ mol-1
  • Inversely proportional to the distance between two charged groups
  • Broken by changes in pH or high ionic strength
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17
Q

How do hydrophobic interactions come to be?

A

They are non-polar side chains of AAs forced together in aqueous environments in order to minimise their disruptive effect on the H-bonding network of water molecules.

18
Q

Where on a protein do charged/polar residues normally map to in soluble proteins?

A

The surface of soluble proteins, inc. hydrophilic residues.

19
Q

Where in a protein do non-polar residues normally map to in a soluble protein?

A

To the hydrophobic core; non-polar/hydrophobic AAs grouped here away from direct contact with H2O.

20
Q

Can soluble proteins have hydrophobic surface regions?

A

Yes; hydrophobic regions are not only present in the centre. Exposed surface hydrophobic side chains form surfaces for protein-protein interactions, with exposed residues forming ligand binding clefts such as active sites in enzymes.

21
Q

How do proteins undergo folding to a stable low energy conformation?

A
  • Folding begins w/formation of local segments of secondary structure
  • A ‘molten globule’ can form by ‘hydrophobic collapse’; all hydrophobic side chains suddenly clumping together
  • This is where the secondary structure elements of the protein are mostly formed
  • Burial of hydrophobic side chains, exposure of polar/charged side chains to form H-bonds w/water, H-bonding and salt-bridging interactions.
22
Q

What are chaperone proteins?

A

They assist in the proper folding of proteins in the cell via directed pathways etc

23
Q

How are proteins denatured?

A

Extreme changes of pH, temperature or chemical agents such as detergents.

24
Q

What is the result of amyloid/fibril formation?

A

These are non-native/abnormal structures that can cause the build-up of aggregates e.g. amyloid in Alzheimer’s Disease (changes in secondary structure?)

25
Q

What effect can single AA substitution/deletion have on the folding and stability of a protein?

A

Significant changes; e.g. cystic fibrosis is caused by altered protein folding; a mutation in the gene cystic fibrosis transmembrane conductance regulator (CFTR).

26
Q

How does cystic fibrosis affect blood glucose control?

A
  • Do not make enough insulin

- Cystic fibrosis-related diabetes (CFRD) shares characteristics found in type 1 & 2 diabetes

27
Q

What is sickle cell disease caused by?

A
  • Single coding change mean Val is coded for instead of Glu (normally acidic)
  • Results in an exposed hydrophobic region
28
Q

What types of changes do proteins undergo upon activation?

A
  • Small scale conformational changes
  • Domain motions
  • Induced fit to bind substrates or other proteins
29
Q

How was the three-dimensional structure of insulin discovered?

A

Via X-ray crystallography by Dorothy Crowfoot Hodgkin in 1969

30
Q

What form does insulin mostly exist in dilute solutions such as circulation?

A

Monomeric; the biologically active form

31
Q

How does insulin exist in crystals and β-cell secretory granules?

A

Hexamers

32
Q

What conditions do hexamers of insulin form?

A
  • pH (around 5.5)

- Presence of zinc and calcium ions (dimers associated to hexamers in presence of zinc)

33
Q

When does insulin dimerize?

A

At micromolar concentrations

34
Q

What occurs to insulin hexamers upon extracellular release?

A

Hexamers dissociate into dimers and eventually into monomers; the biologically active form.

35
Q

Under what conditions do insulin amyloid fibrils form?

A
  • Under solution conditions when the native form is destabilised
  • Largely helical polypeptide insulin readily aggregates to form amyloid fibrils
36
Q

What are the complications for insulin fibrillation in therapeutics?

A

Fibrillation process can interfere with requirement of equal amounts of functional insulin in each dose

37
Q

What is the mechansim of insulin fibril formation?

A

Insulin monomer undergoes partial unfolding before converting into mature fibrils

38
Q

What is noteworthy regarding the surface of insulin?

A
  • Two extensive non-polar (hydrophobic) surfaces
  • First is aromatic and buried upon dimer formation
  • Second is buried upon hexamer formatoin
  • Same surfaces used to bind to its cognate receptor as well as self-assembly
39
Q

What is different about rapid-acting analogues and how can they be beneficial?

A
  • Proportion bound in the form of hexamers/dimers is lower

- Monomeric form of the molecule can be absorbed at the point of injection (SC) more quickly

40
Q

List some examples of rapid-acting insulin analogues.

A
  • Insulin lispro
  • Insulin aspart
  • Insulin glulisine
41
Q

How does the rapid-acting analogue insulin aspart achieve its rapid-acting status?

A
  • Proline 28 (apolar) in the B-chain is substituted with an Aparctic Acid residue (charged, negative)
  • This increased charge repulsion, preventing hexamer formation

RED - Chemistry (3 decks)

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